Abstract
Autophagy-related gene-5 (ATG-5) is one of the key regulators of autophagic cell death. It has been widely regarded as a protective molecular mechanism for tumor cells during the course of chemotherapy. In the present study, we investigated the expression pattern of ATG-5 and multidrug resistance-associated protein-1 (MRP-1) in 135 gastric cancers (GC) patients who were treated with epirubicin, cisplatin and 5-FU adjuvant chemotherapy (ECF) following surgical resection and explored their potential clinical significance. We found that both ATG-5 (77.78%) and MRP-1 (79.26%) were highly expressed in GC patients. ATG-5 expression was significantly associated with depth of wall invasion, TNM stages and distant metastasis of GC (P<0.05), whereas MRP-1 expression was significantly linked with tumor size, depth of wall invasion, lymph node metastasis, TNM stages and differentiation status (P<0.05). ATG-5 expression was positively correlated with MRP-1 (rp = 0.616, P<0.01). Increased expression of ATG-5 and MPR-1 was significantly correlated with poor overall survival (OS; P<0.01) and disease free survival (DFS; P<0.01) of our GC cohort. Furthermore, we demonstrated that ATG-5 was involved in drug resistant of GC cells, which was mainly through regulating autophagy. Our data suggest that upregulated expression of ATG-5, an important molecular feature of protective autophagy, is associated with chemoresistance in GC. Expression of ATG-5 and MRP-1 may be independent prognostic markers for GC treatment.
Highlights
Despite a considerable decline in its incidence rate in many developed countries, gastric cancer (GC) remains the fourth most commonly diagnosed malignancy, and the second leading cause of cancer-related deaths worldwide [1]
Expression of Autophagy-related gene-5 (ATG-5) and multidrug resistance-associated protein-1 (MRP-1) in GC The expression pattern and location of ATG-5 and MRP-1 in our GC patients, who were treated with epirubicin, cisplatin and
The data showed that both ATG-5 and MRP-1 were positively expressed in cancer and non-cancerous tissues, which suggest that ATG-5 and MRP-1 may be induced by chemotherapy in both tumor and nontumor tissues
Summary
Despite a considerable decline in its incidence rate in many developed countries, gastric cancer (GC) remains the fourth most commonly diagnosed malignancy, and the second leading cause of cancer-related deaths worldwide [1]. Autophagy is a lysosomedependent self-digesting system primarily responsible for removal and recycling of long-lived proteins and damaged/obsolete intracellularorganelles in order to maintain cell homeostasis [3]. It has been documented that autophagy could be induced in response to many unfavorable conditions including nutrient deprivation, oxidative stress or DNA damages and serves as an adaptive cell mechanism, eventually allowing cells to survive and proliferate, while extensive or persistent autophagy results in cell death [5]. Li and colleagues reported that autophagy was activated as a protective mechanism against the cellular effects of 5-FU-treatment and inhibition of autophagy by 3-methyladenine augmented 5-FU-induced apoptosis in colon cancer cells [7,8]. Some anticancer drugs (e.g. cetuximab and dasatinib) were demonstrated to induce autophagic cell death through different mechanisms in some cancer cells [9–
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